This proposal addresses the cellular and molecular mechanisms by which modified self-protein specific effector T cell (Teff) subsets modulate neurodegeneration in models of Parkinson's disease (PD). Increasing evidence suggests that neurotoxic inflammatory activities affect pathogenesis and progression of PD. Neuroinflammatory processes also produce oxidized and modified self-central nervous system (CNS) proteins which lead to dysfunction, mis-folding, aggregation, and retention of those oxidized products. In PD, nitrated ?-synuclein (N-?-syn) is found aggregated within the cytoplasm and Lewy bodies of dopaminergic neurons within the substantia nigra and is release to the extraneuronal environment by dying and damaged neurons. Previous studies have shown that after 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) intoxication, adoptive transfer of Teffs exacerbates microglial-mediated neuroinflammation and amplifies dopaminergic neurodegeneration with accelerated and prolonged neuropathology. Additionally, Teffs that secrete IL-17 (Th17 type) exacerbate neurodegeneration to greater levels than those Teff types that secrete IFN-c (Th1 type). Thus, we posit that N-?-syn specific Th17 effector T cells exacerbate neurodegeneration indirectly via hyperactivation of microglial-mediated neurotoxicity or alternatively by direct cytotoxicity of neurons. In order to test this hypothesis we will first determine whether N-?-syn specific effector T cells mediate neurotoxicity via exacerbation of microglia or by direct cytotoxicity to dopaminergic neurons by generating a N-?-syn specific Th17 effector T cell line and testing this line in in vitro cultures with both neurons and microgli to determine neuron cell survival and toxicity. We will then determine whether cell-to-cell contact or proinflammatory cytokines are required for Th17-mediated exacerbation of neurodegeneration with the use of co-cultures composed again of Th17 effector T cells, microglia, and neurons. These co-cultures will be configured with the cells in either direct contact or transwell configurations in order to determine the necessity of direct cell-to-cell contact by T cells to exacerbate their neurodegenerative effects. Lastly we will validate the mechanisms of specific factors linked to the exacerbation of neuroinflammatory and neurodegenerative Th17- mediated responses to test said factors we will target those factors in animal models of PD as well as utilize antibody blocking assays, siRNA, and transgenic models to block Th17-mediated exacerbation of neuroinflammation or neurodegeneration. These experiments, taken together, will permit novel insight into how N-?-syn specific effector T cells induce neurodegeneration in models reflective of Parkinson's disease.